2.1. PERIPHERAL NEUROPATHIES
A patient who exhibits a disorder of one or more peripheral nerves is said to suffer from a peripheral neuropathy. Peripheral nerves extend beyond the brain and spinal cord into tissues that lie outside the central nervous system to provide a bidirectional communication network. They serve as conduits of impulses from the brain and spinal cord to the rest of the body; for example, motor neurons carry signals to direct movement. Peripheral nerves are also capable of transmitting sensory information gathered by specialized receptors to the brain. In short, peripheral nerves provide the connection between brain, body, and environment, and serve to coordinate the relationship between an organism's brain and the outside world.
A peripheral neuropathy may manifest itself in a number of ways. If a motor nerve is affected, the patient may exhibit weakness in the muscle groups supplied by that nerve. If a sensory nerve is involved, the patient may experience numbness, tingling, loss of sensitivity to temperature, touch, and/or vibration, or even increased sensitivity in the area innervated by the diseased nerve.
Numerous varieties of peripheral neuropathy exist. Some are common, others are extremely rare. The etiology of certain peripheral neuropathies is well understood but some remain a mystery. Many neuropathies have been classified into particular syndromes. Each syndrome is associated with its own set of clinical symptoms and signs, prognosis, and treatment options. It is extremely important to be able to match a particular patient with the syndrome that corresponds to his or her clinical condition. Such matching, like a road map, permits the physician to choose a course of treatment and to counsel the patient as to prognosis. Often the identification of a syndrome alerts the physician to another medical condition associated with the patient's peripheral neuropathy which requires a particular course of treatment and carries its own prognosis. Accordingly, the ability to make a correct and precise diagnosis is exceedingly important in the management of a patient suffering from a peripheral neuropathy. Making the correct diagnosis may, however, be difficult. In the past, such diagnosis has depended upon an analysis of the patient's symptoms and an extremely detailed physical examination. To further complicate matters, many peripheral neuropathy syndromes have not yet been fully characterized.
Peripheral neuropathies may appear as manifestations of a wide variety of disease processes, including genetic, traumatic, metabolic, immune, and vascular disorders, as shown by Table I (see, for review, Plum and Posner, 1985, in "Pathophysiology The Biological Principles of Disease," Smith and Thier, eds., Second Edition, W. B. Saunders Co., Philadelphia, Pa., pp. 10851090).
TABLE I ______________________________________ ANATOMIC CLASSIFICATION OF PERIPHERAL NEUROPATHY TWO OVERALL TYPES 1. SYMMETRICAL GENERALIZED 2. FOCAL AND MULTIFOCAL ______________________________________ 1. Symmetrical Generalized Neuropathies (Polyneuropathies) Distal Axonopathies Toxic - many drugs, industrial and environmental chemicals Metabolic - uremia, diabetes, porphyria, endocrine Deficiency - thiamine, pyridoxine Genetic - HMSN II Malignancy associated - oat-cell carcinoma, multiple myeloma Myelinopathies Toxic - diphtheria, buckthorn Immunologic - acute inflammatory polyneuropathy (Guillain-Barre), chronic inflammatory polyneuropathy Genetic - Refsum disease, metachromatic leukodystrophy Neuronopathies somatic motor Undetermined - amyotrophic lateral sclerosis Genetic - hereditary motor neuronopathies somatic sensory Infectious - herpes zoster neuronitis Malignancy-associated - sensory neuronopathy syndrome Toxic - pyridoxine sensory neuronopathy syndrome Undetermined - subacute sensory neuronopathy syndrome autonomic Genetic - hereditary dysautonomia (HSN IV) 2. Focal (Mononeuropathy) and Multifocal (Multiple Mononeuropathy) Neuropathies Ischemia - polyarteritis, diabetes, rheumatoid arthritis Infiltration - leukemia, lymphoma, granuloma, Schwannoma, amyloid Physical injuries - severance, focal crush, compression, stretch and traction, entrapment Immunologic - brachial and lumbar plexopathy ______________________________________
Neuropathies may be classified on the basis of the anatomic component of peripheral nerve most affected. For example, some peripheral neuropathies, such as Guillain-Barre syndrome, which is associated with inflammation of peripheral nerve, is classified as a demyelinating neuropathy because it is associated with destruction of the myelin sheath that normally surrounds the nerve cell axon. In contrast, axonal neuropathies result from damage to the axon caused either by direct injury or, more commonly, from metabolic or toxic injury. In axonal neuropathy, the myelin sheaths disintegrate, as in demyelinating neuropathy, but myelin loss is secondary to deterioration of the axon. Still other neuropathies, classified as neuronopathies, are caused by degeneration of the nerve cell body; examples include amyotrophic lateral sclerosis and herpes zoster neuronitis.
Peripheral neuropathies are also classified according to the distribution of affected nerves. For example, as shown in Table I, some neuropathies are symmetrically, generally distributed, whereas others are localized to one or several areas of the body (the focal and multifocal neuropathies).
Yet another characteristic used to categorize peripheral neuropathies is the nature of the patient's symptoms, i.e., whether the patient suffers predominantly from sensory or motor abnormalities. Some peripheral neuropathies, such as amyotrophic lateral sclerosis (ALS) and the recently described Multifocal Motor Neuropathy (MMN) with conduction block are associated primarily with motor dysfunction. Others, such as paraneoplastic sensory neuropathy and neuronopathy associated with Sjogren's syndrome, are manifested by sensory abnormalities.
A brief description of several disorders of peripheral nerves as follows.
2.1.1. AMYOTROPHIC LATERAL SCLEROSIS
Of the predominantly anterior horn cell (AHC) disorders, amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) is the most common (see Williams and Windebank, 1991, Mayo Clin. Proc. 66:54-82 for review).
The initial complaint in most patients with ALS is weakness, more commonly of the upper limbs (Gubbay et al., 1985, J. Neurol. 232:295-300; Vejjajiva et al., 1967, J. Neurol. Sci. 4:299-314; Li et al., 1988, J. Neurol. Neurosurg. Psychiatry 51:778-784). Usually the early pattern of weakness, atrophy, and other neurological signs is asymmetric and often focal (Munsat et al., 1988, Neurol. 38:409-413). Muscle cramps, paresthesia (tingling sensations) and pain are frequent complaints (Williams and Windebank). Widespread fasciculations are usually present (id.). The rate of progression of the disease varies from patient to patient (Gubbay et al., 1985, J. Neurol. 232:295-300), but in virtually all cases the disease eventually results in complete incapacity, widespread paralysis (including respiratory paralysis) and death.
Anatomically, the most prominent changes are atrophy of the spinal cord and associated ventral roots and firmness of the lateral columns (hence the name, amyotrophic lateral sclerosis; Williams and Windebank). Upper motor neurons are also involved and degenerate in ALS. The brain may appear normal macroscopically, although atrophy of the motor and premotor cortices is usually present due to upper motor neuron involvement. There is widespread loss of Betz cells and other pyramidal cells from the precentral cortex, with consequent reactive gliosis (Hammer et al., 1979, Exp. Neurol. 63:336-346).
Current treatment consists of symptomatic therapy to diminish muscle cramps, pain, and fatiguability. Prosthetic devices are used to compensate for muscle weakness. Pharmacologic therapy to alter the progress of the disease has, however, been largely unsuccessful. Putative therapeutic benefits of thyrotropin releasing hormone have met with conflicting results (Brooks, 1989, Ann. N.Y. Acad. Sci. 553:431-461). Administration of gangliosides has been ineffective (Lacomblez et al., 1989, Neurol. 39:1635-1637). Plasmapheresis has shown no therapeutic advantage, either alone or in combination with immunosuppressive treatment (Olarte et al., 1980, Ann. Neurol. 8:644-645; Kelemen et al., 1983, Arch. Neurol. 40:752-753). The antiviral agent guanidine was reported to have potential short-term benefits, but the results were not reproducible (Munsat et al., 1981, Neurol. 31:1054-1055). Administration of branched-chain amino acids to activate glutamate dehydrogenase was reported to slow the rate of decline of patients in an abbreviated study (Plaitakis et al., 1988, Lancet 1:1015-1018). Most recent therapeutic trials, some in progress, involve whole-body total lymphoid irradiation, the use of amino acids N-acetyl-cysteine, N-acetylmethionine, L-threonine, and long-term intrathecal infusion of thyrotropin releasing hormone (Williams and Windebank).
Animal models that bear clinical and pathologic resemblances to ALS include the MND mouse, an autosomal dominant mutant exhibiting late-onset progressive degeneration of both upper and lower motor neurons (Messer and Flaherty, 1986, J. Neurogen. 3:345-355); the wobbler mouse, that exhibits forelimb weakness and atrophy in early life due to muscle denervation, and hereditary canine spinal muscular atrophy in the Brittany spaniel (Sack et al., 1984, Ann. Neurol. 15:369-373; Sillevis et al., 1989, J. Neurol. Sci. 91:231-258; Bird et al., 1971, Acta Neuropathol. 19:39-50).
2.1.2. MULTIFOCAL MOTOR NEUROPATHY WITH CONDUCTION BLOCK
In previous years, patients suffering from multifocal motor neuropathy (MMN) with conduction block were often considered to have pure motor forms of chronic inflammatory demyelinating polyneuropathy (CIDP) or lower motor neuron (LMN) forms of ALS (Bird, 1990, Current Opinion Neurol. Neurosurg. 3:704-707). MMN has recently been characterized as a distinct clinical syndrome. MMN appears to be characterized clinically by asymmetric, progressive, predominantly distal limb weakness; arms are involved more frequently than legs and there is generally no bulbar, upper motor neuron, or sensory involvement (id.). In more than eighty percent of patients the weakness begins in the hands and may progress slowly for periods up to twenty years. MMN is more common in males than females (2:1) and frequently (66 percent) begins in patients younger than 45 years of age. Nerve conduction studies show evidence of multifocal conduction block on motor but not on sensory axons (Chad et al., 1986, Neurology 36:1260-1266; Parry and Clarke, 1988 Muscle Nerve 11:103-107; Pestronk et al., 1988, Ann. Neurol. 24:73-78).
Patients suffering from MMN appear not to improve clinically with corticosteroid therapy; Pestronk et al. (1990, Ann. Neurol. 27:316-326) noted improvement in only one out of seven patients treated with high-dosage prednisone; treatment with cyclophosphamide appeared to be more successful. Pestronk et al. (1989, Neurology 39:628-633) have suggested that prednisone and cyclophosphamide may exert different effects on autoantibodies in neuromuscular disorders.
MMN may be distinguishable from another motor neuropathy syndrome that more clearly meets criteria for a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Although both are predominantly motor neuropathies, MMN and motor CIDP differ in their clinical features, physiologic changes, serologic findings and response to immunosuppression. In contrast to MMN, patients with motor CIDP usually have symmetric weakness that involves proximal muscles early in the course of the disease. While nerve conduction studies in CIDP may show evidence of conduction block, there is often evidence of more diffuse demyelination on both motor and sensory axons. Physiologic changes in motor CIDP that are found in only a minority of patients with MMN include slowing (less than 70% of normal) of conduction velocities, and prolonged distal latencies to the range found in demyelinating disorders. High titers of IgM anti-GM1 ganglioside antibodies are only rarely found in motor CIDP patients. A further contrast to MMN is the response to treatment. As has been reported for the overall population of CIDP patients, those with motor CIDP often demonstrate increased strength within a few weeks to months after treatment with prednisone, plasmapheresis or intravenous human immune globulin.
2.1.3 DISTAL LOWER MOTOR NEURON SYNDROME
Distal Lower Motor Neuron (LMN) Syndrome has a clinical syndrome of slowly progressive, distal and asymmetrical weakness that begins in a band or foot which is similar to that of MMN (1991 Muscle & Nerve 14: 927-936). However, distal LMN begins more frequently in the legs than MMN and there is an absence of motor conduction block in physiologic studies of distal LNM. Id.
Patients with distal LMN syndromes, particularly those in the early stages of the disease or with preserved reflexes in areas of weakness, may be difficult to distinguish from patients with ALS. Id. Distal LMN differs clinically from ALS in that distal LMN progresses more slowly that ALS, patients with distal LMN lack very brisk (4+) reflexes, and there is a general absence of bulbar dysfunction. Id.
Fifty-five percent of distal LMN patients have high titers of serum IgM anti-GM1 ganglioside antibodies, and 15% to 20% of antibody-positive patients have an associated serum IgM-protein. Id.
Some patients with distal LMN and high anti-GM1 ganglioside antibody titers improve after treatment with cyclophosphamide or chlorambucil. However, they respond less frequently to immunosuppression than patients with MMN.
2.1.4. SENSORY NEUROPATHIES
A variety of neuropathies are primarily sensory in nature, including leprous neuritis, sensory perineuritis, hyperlipidemic neuropathies, certain amyloid polyneuropathies, and distal symmetrical primary sensory diabetic neuropathy. These are primary axonal or demyelinating neuropathies.
In addition, pure sensory syndromes, known as sensory neuronopathies, have been identified that result from primary pathological events in the dorsal root ganglion or trigeminal cell bodies (Asbury and Brown, 1990, Current Opinion Neurol. Neurosurg. 3:708-711; Asbury, 1987, Semin. Neurol. 7:58-66). Some examples of sensory syndromes follow.
A severe subacute primary sensory neuropathic disorder may occur in the context of concurrent malignancy, particularly small-cell lung cancer, and may in fact precede the diagnosis of malignancy (Asbury and Brown).
Sjogren's syndrome, characterized by dry mucous membranes and skin and the destruction of salivary and lacrimal glands, appears to be associated with a sensory neuronopathy. Griffin et al. (1990, Ann. Neurol. 27:304-315) found that eleven women and two men with undiagnosed ataxic sensory neuronopathy and autonomic dysfunction all had primary Sjogren's syndrome.
Furthermore, hundreds of commonly encountered chemicals, including environmental toxins, vitamins, and various prescription drugs, can cause a polyneuropathy that begins as a distal symmetrical sensory neuropathy and may progress to a mixed sensory-motor-autonomic disorder. Examples of such chemicals include cis-platinum (Mollman, 1990, N. Engl. J. Med. 322:126-127), vitamin B. (Xu et al., 1989, Neurology 39:1077-1083), taxol (Lipton et al., 1989, Neurology 39:368-373) and doxorubicin (in experimental animals) (Asbury and Brown).
However, the majority of predominantly sensory neuropathies in patients remain undiagnosed.
2.2. ANTIGENIC STRUCTURES OF THE PERIPHERAL NERVOUS SYSTEM
There is increasing evidence that serum antibodies directed against glycolipids or glycoproteins (Table II) commonly occur in high titer in patients with some forms of motor neuron disease and peripheral neuropathy. This association was first noted in patients with chronic demyelinating neuropathies who had monoclonal IgM serum antibodies that reacted with myelin-associated glycoprotein. It is now apparent that high titers of serum antibodies to GM1 ganglioside commonly occur along with lower motor neuron (LMN) diseases and motor neuropathies. Antineuronal antibodies in serum and CSF have been identified in patients with sensory ganglionopathies and small-cell lung neoplasms. We will review the association of clinical neuromuscular syndromes with antibodies that react with glycolipids and structurally related glycoproteins.
TABLE II ______________________________________ COMMON ANTIGENIC TARGETS IN NEUROPATHY SYNDROME PATIENTS Compound Structure ______________________________________ GM1 Gal.beta.1-3GalNAc.beta.1-4Gal.beta.1-4Glc.beta.1-1'Ceramide 3Neu5Ac.alpha.2 GA1 Gal.beta.2-3GalNAc.beta.1-4Gal.beta.1-4Glc.beta.1-1'Ceramide GM2 GalNAc.beta.1-4Gal.beta.1-4Glc.beta.1-1'Ceramide 3 Neu5Ac.alpha.2 Sulfatide SO.sub.4 -3-Gal.beta.1-1'Ceramide MAG SO.sub.4 -3-Glucuronic Acid - antigenic epitope and SGPG ______________________________________ Common antigenic targets in neuropathy syndrome patients. Structures of GM1 ganglioside, asialoGM1 ganglioside (GA1), and GM2 ganglioside are illustrated. The gangliosides GM1 and GM2 consist of a) a lipid component ceramide, b) a carbohydrate moiety (3 sugars for GM2, 4 sugars for GM1) that includes galactose (Gal), galactosamine (GalNAc) and glucose (Glc), and c) a sialic acid ganglioside. GD1a has an additional sialic acid attached to the terminal galactose on GM1. # GD1b has a second sialic acid attached to the sialic acid on GM1. GT1B has additional sialic acid in both locations.
2.2.1. GANGLIOSIDES
Gangliosides are a family of acidic glycolipids that are composed of lipid and carbohydrate moieties (Table II). The lipid moiety, ceramide, is a fatty acid linked to a long chain base, sphingosine. In mammalian brain gangliosides, the sphingosine contains 18-20 carbon atoms. The carbohydrate portion of gangliosides is a series of 2 or more sugars with at least one sialic acid. The major gangliosides in mammalian brain contain 1-3 sialic acids, usually N-acetylneuraminic acid contain 1-3 sialic acids, usually N-acetylneuraminic acid (Neu5Ac), and a chain of 2-4 other sugars. Four gangliosides are especially abundant in brain, namely GM1, GD1a, GD1b and GT1b. They each contain the same 4 sugar chain (Table II) but vary in the number of sialic acid molecules; GM1 ganglioside with one, GD1 1a and GD1b with two and GT1b with three. In peripheral nerve a fifth ganglioside, LM1, containing a different carbohydrate structure, also occurs in relative abundance. Numerous minor gangliosides in brain, nerve and myelin have been described. Gangliosides generally reside in the outer layer of plasma membrane. The hydrophilic sugars are located on the outer surface of the membrane. They are linked to the cell by the hydrophobic lipid moiety which is inserted into the membrane.
GM1 ganglioside is one of the most abundant gangliosides in neuronal membranes but is unusual outside of the nervous system. It has been postulated that gangliosides may play a role in membrane and cell functions. There is a large amount of literature suggesting that administration of exogenous GM1 ganglioside enhances neurite outgrowth and recovery from injury. GM1 ganglioside and other gangliosides can function as cellular receptors. The binding of cholera toxin to GM1 ganglioside is well documented. Gangliosides on nerve terminals may also serve as receptors for tetanus and botulinum toxins.
The abundance of gangliosides in the nervous system and the extracellular location of their sugars suggests that they could be antigenic targets in autoimmune neurological disorders. The terminal disaccharide on GM1 ganglioside, Gal.beta.-3GalNAc, is known to be antigenic when it occurs on systemic glycoproteins. However, the disaccharide on these glycoproteins is normally hidden from immune attack by a sialic acid attached to each sugar. Several investigators have tested sera from presumed autoimmune disorders for antibody binding to panels of gangliosides looking for possible targets of the immune processes.
2.2.2. MYELIN-ASSOCIATED GLYCOPROTEIN
Myelin-associated glycoprotein (MAG; Table II) is a nervous system-specific protein that is found in both the central and peripheral nervous systems. It is present in myelin related membranes but not the compact myelin of oligodendrocytes and Schwann cells. MAG is an integral membrane protein. Almost one third of its molecular weight is due to the post-translational addition of carbohydrate molecules. The terminal sulfated glucuronic acid carbohydrate moieties in MAG are important because they are the main targets of IgM paraprotein antibody reactivity. MAG has structural similarities to immunoglobulins and to cell adhesion molecules. MAG is thought to mediate adhesive and trophic interactions between cell membranes during myelin formation and maintenance. Sulfated glucuronic acid epitopes also occur on peripheral nerve glycolipids including sulfated glucuronal paragloboside (SGPG) and a group of glycoproteins of molecular weight 19,000 to 28,000.
2.2.3 HISTONE H3
Histone H3 is a member of a family of basic DNA proteins which are arranged in nucleosomal particles, subcomponents of chromatin. Histone H3 is found in the inner core of nuclesomes. The protein is composed of 134 amino acid residues. An unmodified chain of histone H3 has a molecular weight of 15,117.
2.3. ANTIBODIES IN PERIPHERAL NEUROPATHIES
There has been a growing appreciation that many neurologic disorders may have an autoimmune basis. This realization has occurred in conjunction with an increasing knowledge of the molecular specificities of autoantibodies (Steck, 1990, Neurology 40:1489-1492). Consequently, the role of antibody testing as part of the neurologic diagnostic process has become progressively more important.
2.3.1. ANTI-GM1 GANGLIOSIDE ANTIBODIES
Pestronk et al. (1990, Ann. Neurol. 27:316-326) reports a study of sera from 74 patients with lower motor neuron syndromes. Antibody specificities were compared to clinical and electrophysiological data in the same patients. Several distinct lower motor neuron syndromes were identified based on clinical, physiological, and antiglycolipid antibody characteristics. The results indicated that antibodies to ganglioside GM1, to similar glycolipids, and to carbohydrate epitopes on GM1 ganglioside and GA1 may be common in sera of patients with lower motor neuron syndromes.
Similarly, Nobile-Orazio et al. (1990, Neurology 40:1747-1750) reports a study that compared anti-GM1 ganglioside IgM antibody titers by enzyme-linked immunosorbent assay in 56 patients with motor neuron disease, 69 patients with neuropathy, and in 107 control subjects. Anti-GM1 ganglioside IgM antibodies were found in 13 (23 percent) of motor neuron disease patients, 13 (18.8 percent) neuropathy patients, and 8 (7 percent) of controls. Two of the 13 neuropathy patients exhibiting anti-GM1 antibody also were found to have antibodies directed toward MAG protein.
It appears that high titers of serum IgM anti-GM1 ganglioside antibodies (present at dilutions of &gt;350-400) occur commonly in some motor neuron and peripheral neuropathy syndromes but not in others (Table III). The highest titers (&gt;7,000) are especially specific for lower motor neuron syndromes and multifocal motor neuropathy. Low titers of anti-GM1 ganglioside antibodies (&lt;350) are not specific. They may be found in sera from patients with a variety of neurologic and autoimmune disorders as well as from some normal controls.
TABLE III ______________________________________ IgM ANTI-GM.sub.1 ANTIBODIES - CLINICAL ASSOCIATIONS ______________________________________ 1) Frequently (&gt;50%) present in high titer (&gt;350): Multifocal motor neuropathy Distal lower motor neuron syndromes 2) Occasionally (5-15%) present in high titer: Proximal lower motor neuron syndromes ALS Guillain-Barre Syndrome Polyneuropathies = especially motor-sensory & asymmetric Autoimmune disorders without neuropathy 3) Rarely (&lt;5%) present in high titer: CIDP Sensory neuropathies & neuronopathies Normals (&lt;1%) ______________________________________
2.3.2. ANTI-MAG ANTIBODIES
High titers of serum antibodies directed against MAG are commonly associated with a slowly progressive demyelinating peripheral neuropathy. In 40-50% of patients with IgM monoclonal gammopathy and neuropathy, the M-protein reacts with MAG. The clinical syndrome related to high titers of serum anti-MAG antibodies is a distal symmetric neuropathy involving both sensory and motor modalities. Symptoms usually begin distally and symmetrically in the feet and legs. The hands are commonly also affected. Unlike another demyelinating neuropathy, CIDP, weakness only involves proximal musculature late in the disorder. Sensory findings usually include large fiber dysfunction, with sensory ataxia in severe cases. The neuropathy is slowly progressive and may apparently stabilize for long periods at a point of severe, or only mild, dysfunction. A majority of patients with IgM anti-MAG related polyneuropathy are male (&gt;80%). Most are older than 50 years of age. Electrophysiological studies usually are indicative of demyelination. The most consistent finding is prolonged distal latencies. Conduction velocity slowing, temporal dispersion and increased F-response latency are also seen. Cerebral spinal fluid (CSF) protein concentration is often elevated. Sera with very high titers of IgM anti-MAG activity show evidence of a monoclonal IgM in many cases, if sensitive screening methods, such as immunofixation, are used. In contrast, patients with predominantly sensory neuropathies, or those that are primarily axonal, only rarely have high-titer serum IgM reactivity to MAG (Nobile-Orazio, et al., 1989, Ann. Neurol. 26:543-550; Dubas et al., 1987, Cas. Rev. Neurol. (Paris) 143:670-683.
A common feature of the anti-MAG antibodies in demyelinating sensory motor neuropathy syndromes is cross reactivity with compounds that, like MAG, contain sulfate-3-glucuronate epitopes. These compounds include myelin components such as the P.sub.o glycoprotein (Bollensen et al., 1988, Neurology 38:1266-1270; Hosokawa et al., 1988, In Neuroimmunological Diseases," A. Igata, ed. Tokyo: University of Tokyo Press, pp. 55-58) and an acidic glycolipid, sulfate-3-glucuronyl paragloboside (SGPG) (Nobile-Orazio; Ilyas et al., 1985, Proc. Natl. Acad. Sci. U.S.A. 82:6697-6700; Chou et al., 1986, J. Biol. Chem. 261:11717-11725; Ariga et al., 1987, J. Biol. Chem. 262:848-853).
2.3.3. ANTI-HISTONE H3 ANTIBODIES
Antibodies to Histone H3 have been described in patients with a variety of autoimmune diseases. In particular, high titers of serum antibodies directed against histone H3 are strongly associated with chronic iridocyclitis.